Systematic study of cellular cholesterol homeostasis

胆固醇是一种营养素，在哺乳动物细胞膜的生理学中起着核心作用。由于其独特的生物物理性质，胆固醇可以迅速插入细胞膜，建立一种功能屏障，这对于确保细胞参与维持生命的生物活动的动态平衡环境至关重要。重要的是，胆固醇使这些影响的水平在不同类型的膜(即。质膜和内质网膜)，即使这些膜特定水平的微小偏差也会导致细胞应激和损伤，并可能导致病理和致命后果。换句话说，哺乳动物动物的生存取决于动物体内细胞膜的能力，即能够避免胆固醇过少和过多，而且每种类型的细胞膜都有不同的阈值。这种具有挑战性的代谢限制表明，协调胆固醇稳态以确保膜稳态的机制是一种基本的进化关系。尽管胆固醇在细胞膜上的重要作用是众所周知的，但将胆固醇的丰度和分布不均匀与膜的动态平衡联系起来的细胞机制却知之甚少。我对NSERC资助的研究项目的长期愿景是定义这些机制背后的分子参与者和作用模式，并利用这些洞察力来确定其进化起源，并预测这一过程可能如何受到环境压力的影响，如营养挑战、污染和气候变化。在这个项目的初始阶段，我的团队将开始系统地识别调节内质网膜中胆固醇水平的蛋白质，并确定这些蛋白质确保细胞内稳态的机制基础。之所以关注内质网，是因为内质网是调节细胞内胆固醇稳态的关键部位，也是维持胆固醇浓度阈值面临独特挑战的细胞器。因此，我预测内质网配备了专门的防御机制，限制胆固醇的稳态水平。上述研究将在细胞培养模型系统上进行，该系统在胆固醇代谢研究中显示出几个优点，并将利用先进的分子技术、系统生物学和生物化学。总之，该项目为学生和研究员提供尖端的技术培训，并为发现显著提高我们对胆固醇稳态和膜生物学的基本理解提供了一个丰富的智力环境。鉴于胆固醇在哺乳动物中的广泛而基本的作用，这种见解可能会在生物科学的广泛学科中产生重大影响。

Cholesterol is a nutrient that plays a central role in the physiology of cell membranes in mammals. Due to its unique biophysical properties cholesterol can rapidly intercalate into membranes to establish a functional barrier, which is essential to secure the homeostatic environment within which cells engage in the biological activities that sustain life. Importantly, the level at which cholesterol renders these effects significantly varies between differing types of membranes (ie. plasma membrane versus endoplasmic reticulum membrane), and even small deviations in these membrane specific levels causes cell stress and damage and can lead to pathological and lethal consequences. In other words, the survival of mammalian animals is dependent on the ability of cell membranes within that animal being able to avoid having too little and having too much cholesterol, and with each type of membrane having a different threshold. Such a challenging metabolic constraint suggests the mechanisms that coordinate cholesterol homeostasis to secure membrane homeostasis underlies a fundamental evolutionary relationship. Though the vital role of cholesterol on membranes is well known, the cellular mechanisms linking cholesterol abundance and non-uniform distribution to membrane homeostasis is poorly understand. My long term vision for an NSERC-funded research program is to define the molecular players and mode of action underlying these mechanisms, and use such insights to identify its evolutionary origin and predict how this process might be impacted by environmental pressures such as nutrient challenges, pollution, and changes in climate. During this initial phase of the program, my group will begin systematically identifying the proteins that regulate cholesterol levels in the endoplasmic reticulum membrane and determine the mechanistic basis by which these proteins secure cellular homeostasis. The reason for focusing on endoplasmic reticulum is that it is well known as a crucial site for coordinating cellular cholesterol homeostasis and as an organelle with unique challenges in maintaining concentration thresholds of cholesterol. Therefore, I predict the endoplasmic reticulum is equipped with specialized defense mechanisms that constrain homeostatic levels of cholesterol. The aforementioned studies will be undertaken on a cell culture model system previously shown to exhibit several advantages for the study of cholesterol metabolism, and will employ advanced molecular techniques, systems biology, and biochemistry. Altogether, this program offers cutting-edge technical training for students and fellows, as well as an enriching intellectual environment for making discoveries that significantly improve our basic understanding of cholesterol homeostasis and membrane biology. Given the broad and fundamental roles of cholesterol in mammals, such insights are likely to have a significant impact across a broad range of disciplines in the biological sciences.